Solid oral anti-tartar and anti-plaque compositions

ABSTRACT

Oral formulations in the form of chewing gum comprising: a. polyphosphates; b. hydrated silica; c. a source of fluoride ions; d. a polymer derived from chitin, or other naturally occurring hydrocolloids or a mixture thereof; e. optionally extracts or active ingredients of vegetable origin and/or antibacterial/disinfectant agents. The compositions of the invention are useful as adjuvants in dental hygiene, in particular to reduce tartar deposits

The present invention relates to oral anti-tartar and anti-plaquecompositions, useful as adjuvants in odontostomatological hygiene.

BACKGROUND TO THE INVENTION

The problem of dental plaque and tartar formation has long been studied,and agents which can be used to combat and delay such formation arebeing actively researched.

The mechanisms that cause tartar deposits are well known; these depositsare constituted by calcium phosphate crystals which precipitate in theextracellular matrix of bacterial plaque. The pathogenetic role oftartar in periodontal diseases such as pyorrhoea, periodontitis,gingivitis and correlated disorders is equally well known.

Various substances have proved effective in reducing or preventingtartar formation and deposits on the teeth, including solublepyrophosphates and polyphosphates, zinc salts, fluorides,diphosphonates, antibacterial agents such as triclosan, and abrasiveagents such as silica or alumina. These substances, combined with oneanother in various ways, are included in the composition of mostanti-tartar toothpastes now commercially available. The clinicalefficacy of these toothpastes has been examined in numerous studies,reviewed in J. Clin. Dent. Vol IV(3), 71-81, 1993.

The most common toothpastes contain soluble polyphosphates associatedwith fluorides and silica, and possibly with polymers that possessbioadhesive properties, as described, for example, in U.S. Pat. No.4,327,977, U.S. Pat. No. 4,889,713, U.S. Pat. No. 5,017,362, U.S. Pat.No. 5,139,769, U.S. Pat. No. 4,921,693 and EP 492997.

Similar compositions, with the addition of antibacterial agents such astriclosan, are described, for example, in GB 2200551. In addition totoothpastes, chewing gums and candies with a similar composition havebeen developed.

The efficacy of these toothpastes, which has been the object of numerousstudies (J. Clin. Dent. Vol. X(3), 99-102, 1999; Oral Surg. Oral Med.Oral Pathol., Vol. 70(4), 529-536, 1990; J. Clin. Dent. Vol. IX(4),101-104, 1998), is due to inhibition of calcium phosphate precipitationby the polyphosphates that complex the calcium ions in the saliva, tothe abrasive action of silica, to the reinforcing effect of fluorides onthe tooth enamel and to the action of bioadhesive polymers, where used,which protects the mucosae and causes slow release of the otheringredients.

The polymers most often used in compositions designed to control tartarare polycarboxylates derived from acrylic or methacrylic acid,particularly copolymers of maleic anhydride with methyl vinyl ether(GANTREX®). However, these polymers are not approved for use infoodstuffs, which means that they can only be used to make toothpastesand mouthwashes.

On the other hand, candies and chewing gum designed as adjuvants indental hygiene and oral hygiene in general, which have properties thatcan be described as anti-tartar, anti-decay, whitening and/orrefreshing, are becoming increasingly popular. The main advantage ofthese forms of administration is that they can be used freely andconveniently during the day in any place and on any occasion, inaddition to that fact that the release of the active elements(functional ingredients) is slower and more regular than in the case ofan ordinary toothpaste.

DESCRIPTION OF THE INVENTION

The present invention relates to oral formulations in a solid form,preferably in the form of chewing gum, whose efficacy is superior tothat of similar known formulations.

The compositions of the invention contain effective amounts of:

-   -   a. polyphosphates, preferably a mixture of alkali metal        pyrophosphates and triphosphates;    -   b. an abrasive agent (preferably hydrated silica);    -   c. a source of fluoride ions;    -   d. a polymer derived from chitin, or other naturally occurring        hydrocolloids or a mixture thereof;    -   e. optionally extracts or active ingredients of vegetable        origin;    -   f. optionally antibacterial or disinfectant agents.

In addition to the active ingredients referred to above, thecompositions of the invention will contain excipients suitable to definethe final form of administration.

Thus, for example, a chewing gum formulation will require a suitablebase consisting of gum base, sweeteners, polyalcohols such as xylitol,sorbitol and mannitol, flavourings, dyes, softeners, plasticisers,stabilisers, thickeners, etc.

The fact that the compositions of the invention comprise a system ableto form a film on the oral mucosa increases protection against tartardeposits, because the active ingredients remain in contact with theuser's teeth and gums for a longer time and the polyphosphates areprotected against the hydrolysing action of the oral cavity.

In the present invention, this system consists of a chitin deacetylatedderivative, possibly chemically modified and optionally in associationwith other polymers, to enhance its bioadhesive properties and itsability to protect the polyphosphates against hydrolysing agents.

There has been great scientific interest in controlled-release systemsdirected at the oral mucosa in the past decade (J. Clin. Phar. Ther.(2000) 25, 21-42). The polymers studied include partly deacetylatedchitin, highly deacetylated chitin or chitosan and hydrolysed chitosanor oligosaccharide, which have proved able to adhere to the tissuesthanks to the positive charges of the ammonium groups. Partly as aresult of their bioadhesive properties, these polymers accelerate woundhealing and haemostasis (Biom. 1999, 20(22): 2139-45; J. Oral. Max.Surg. 57: 49-52). Specific studies demonstrate the bioadhesiveproperties of chitosan towards the oral mucosa (Biom. 16 (1995) 617-624;J. Control Rel. 61: 175-183, Int. J. Pharm. 73: 43-48).

Among the forms described, the preferred form is chitosanoligosaccharide, a commercially available compound that comprises two toseven monomer D-glucosamine units bonded to one another with β-1,4bonds, mainly obtained by enzymatic hydrolysis of chitosan with a highermolecular weight.

Although this procedure is known, it does not appear to have beenapplied in compositions similar to those which are the object of thisinvention.

Optionally, naturally occurring polysaccharides hydrocolloids may beused as alternative with similar bioadhesive properties. Polysaccharideshydrocolloids of this type are: xanthan gum, locust bean gum, alginates,carrageneen, gallan gum and others.

Broadly, the polymer-based system described above amounts to between 0.5and 5% by weight on the total composition, and preferably between 1 and3%.

The polyphosphates used in the compositions may be alkali metalpyrophosphates (diphosphates), hexametaphosphates, tripolyphosphates ormixtures thereof. A mixture of disodium diacid diphosphate andpentasodium or pentapotassium triphosphate is particularly preferred. Ithas been proved that a toothpaste containing this mixture provides amore marked reduction of tartar than a toothpaste containingpyrophosphates not associated with triphosphates (J. Clin. Dent. Vol.IX(4), 101-104, 1998).

Broadly, the polyphosphates amount to between 0.5 and 5% by weight onthe total composition to which the invention relates.

The function of the abrasive agent is to increase the plaque-removingaction already possessed by ordinary chewing gum. It may be formed byhydrated silica (in a suitable form), calcium carbonate (in a suitableform) or talc, either individually or combined with one another. Theseabrasives may also be present totally or partly, either individually orin a mixture thereof, in encapsulated form, in particular encapsulatedin calcium alginate. Chewing gum containing microgranules of hydratedsilica encapsulated in calcium alginate has proved more effective inremoving plaque than a chewing gum with the same formulation but withoutmicrogranules (Doc. Os 06.2001 779-781). According to the presentinvention, the encapsulated microgranules may contain dyes, flavourings,functional ingredients and herb extracts. This abrasive agent is usuallypresent in percentages of between 0.5 and 7% by weight.

Suitable sources of fluoride ions include sodium fluoride, potassiumfluoride, ammonium fluoride, sodium monofluoro-phosphate and other knownnon-toxic salts containing fluorine, in concentrations which providefluoride percentages of between 0.005 and 0.2% by weight.

The vegetable extracts which may be present in the compositions of theinvention will preferably be selected from extracts of Centellaasiatica, Malva sylvestris, Melaleuca alternifolia, Commiphoraabyssinica (myrrh), Krameria triandi (rhatany), Acacia catechu, Medicagosativa (alfalfa), resins of the genus Styrax, such as Styrax benzoin(benzoin), Matricaria recutita (camomile), Echinacea purpurea(echinacea) and Croton lechleri (dragon's blood). Extracts of theseplants, whose activity has been known for some time, are commerciallyavailable.

The combination with these extracts gives the formulationsanti-inflammatory/decongestant, emollient, wound-healing, antiseptic andastringent properties. These properties are desirable in at least tworespects in the ambit of the present invention:

firstly, to assist and reinforce the reduction in diseases of the oralmucosa caused by the reduction in tartar, and

secondly, to control and prevent contact stomatitis similar to thatmanifested with the use of toothpastes, known as “toothpastestomatitis”, in particularly predisposed persons.

In the formulations of the invention, these extracts may be encapsulatedin alginate together with the abrasive agent.

Said extracts may be added to the formulations in percentages of between0.01 and 2% by weight.

The formulations of the invention can be prepared by conventionaltechniques, by adding and mixing the various ingredients to the gum basein the case of chewing gum, which may then undergo coating operations inaccordance with equally conventional techniques.

The formulations of the invention may include disinfectant orantibacterial agents such as triclosan, zinc salts or zinc oxide, eitheralone or combined with one another, in concentrations of between 0.1 and5% by weight. These agents are designed to combat the formation ofbacterial plaque, which leads to tartar deposits.

The formulations of the invention may also include decorative crystals,preferably consisting of gum arabic and dyes deposited on the surface ofthe product with a purely aesthetic function.

Daily use of the chewing gum in accordance with the invention reducestartar deposits and has other beneficial effects on the condition of theoral and gingival mucosa.

The following examples illustrate the invention in greater detail.

EXAMPLE 1 Coated Chewing Gum Weighing 1.4 g

Percentage composition (by weight) Ingredient % Gum base 24.5 Xylitol23.5 Sorbitol 23.2 Mannitol 16 Flavouring 1.8 Silicon dioxide 3 Gumarabic 1 Glycerin 1 Disodium diacid diphosphate 1 Pentasodiumtriphosphate 1 Chitosan oligosaccharide 1 Maltitol syrup 0.93 Titaniumdioxide (E171) 0.7 Quick Coat 0.6 Aspartame 0.6 Decorative crystals 0.05Acesulfame 0.05 Carnauba wax 0.05 Potassium fluoride 0.02 100

EXAMPLE 2 Coated Chewing Gum Weighing 1.4 g with Vegetable Extracts

Percentage composition (by weight) Ingredient % Gum base 24.5 Xylitol23.5 Sorbitol 23.2 Mannitol 16 Flavouring (*) 1.8 Silicon dioxide 3 Gumarabic 1 Glycerin 1 Disodium diacid diphosphate 1 Pentasodiumtriphosphate 1 Chitosan oligosaccharide 1 Maltitol syrup 0.93 Titaniumdioxide (E171) 0.7 Quick Coat 0.6 Aspartame 0.6 Acesulfame 0.05 Carnaubawax 0.05 Potassium fluoride 0.02 Mallow, myrrh, centella, melaleuca,rhatany and 0.05 acacia catechu extracts. Total 100

EXAMPLE 3 Efficacy Tests: Reduction in Tartar Deposit

A double-blind crossover clinical trial has been conducted to comparethe effects of a chewing gum in accordance with Example 1 with those ofa placebo gum.

28 Adults were admitted to the trial and treated with two chewing gumsfor five minutes, four times a day, for 6 weeks. At the end of thisperiod a quantitative evaluation of the tartar deposit was carried outin accordance with the modified Volpe and Manhold index (J. Periodont.Res. (Suppl.) 14:31-60, 1974). Throughout the treatment period, thepatients all used the same toothpaste (not containing anti-tartaragents) and followed a similar diet. The same patients were then treatedfor six weeks immediately after the first evaluation of the tartardeposit with the other chewing gum (Example 1 or placebo) in accordancewith the same treatment procedure as before. At the end of the treatmentperiod a second quantitative evaluation of the tartar deposit wascarried out in accordance with the same procedure as described above.

The results were subjected to statistical analysis using Student'stwo-tailed paired sample “t” test.

The evaluation conducted after the patients had chewed the gum describedin Example 1 demonstrated a 13.9% reduction in tartar deposits comparedwith those observed after chewing of the placebo gum. This reduction isstatistically significant. The results of the study are summarised inTable 1. TABLE 1 “T” test: paired samples for means Placebo Ex. 1 Mean4.2410714 3.6517857 Variance 10.539269 7.9599041 Observations 28 28Pearson's correlation 0.9858011 Hypothesised difference of means 0 P(T<= t) two-tailed 6.884-05

1. Oral formulations in solid form, comprising: a. polyphosphates; b. anabrasive agent; c. a source of fluoride ions; d. a polymer derived fromchitin, or other naturally occurring hydrocolloids or a mixture thereof;e. optionally extracts or active ingredients of vegetable origin; f.optionally antibacterial/disinfectant agents.
 2. Formulations as claimedin claim 1, wherein the polyphosphates are selected fromtripolyphosphates, pyrophosphates or mixtures thereof.
 3. Formulationsas claimed in claim 2, comprising a mixture of alkali metalpyrophosphates and tripolyphosphates.
 4. Formulations as claimed inclaim 1, further containing excipients selected from gum base,sweeteners, polyalcohols, flavourings, dyes, softeners, plasticisers,stabilisers and thickeners.
 5. Formulations as claimed in claim 1,wherein the abrasive agent is hydrated silica, calcium carbonate andtalc, either individually or in a mixture thereof.
 6. Formulations asclaimed in claim 1, wherein the chitin-derived polymer is a (partly ortotally) deacetylated derivative of chitin, optionally chemicallymodified, optionally in association with other polysaccharideshydrocolloids.
 7. Formulations as claimed in claim 6, wherein thepolymer is a chitosan.
 8. Formulations as claimed in claim 7, whereinthe chitosan is chitosan oligosaccharide.
 9. Formulations as claimed inclaim 1, wherein the naturally occurring hydrocolloids are xanthan gum,locust bean gum, alginates, carrageeneens, gellan gum or otherpolysaccharides with bioadhesive properties.
 10. Formulations as claimedin claim 1 containing extracts with anti-inflammatory, wound-healing,antihemorrhagic, soothing, emollient, decongestant and antisepticproperties.
 11. Formulations as claimed in claim 10, wherein thevegetable extracts are selected from extracts of Centella asiatica,Malva sylvestris, Melaleuca alternifolia, Commiphora abyssinica (myrrh),Krameria triandra (rhatany), Acacia catechu, Medicago sativa (alfalfa),resins of the genus Styrax, such as Styrax benzoin (benzoin), Matricariarecutita (camomile), Echinacea purpura (echinacea) and Croton lechleri(dragon's blood).
 12. Formulations as claimed in claim 1, containing 0.5to 5% by weight of polyphosphates, 0.5 to 7% by weight of an abrasiveagent (possibly wholly or partly encapsulated), 0.5 to 5% by weight of apolymer derived from chitin, and a source of fluoride ions able toguarantee a fluoride intake of 0.005 to 0.2%.
 13. Formulations asclaimed in claim 12, further containing 0.01 to 2% by weight ofvegetable extracts.
 14. Formulations as claimed in claim 1, comprisingdisinfectant and/or antibacterial agents selected from triclosan, zincoxide and zinc salts, either alone or in combination with one another,in concentrations of between 0.1% and 5%.
 15. Formulations as claimed inclaim 1, wherein said formulations are chewing gum or candies.